The identification of highly potent broadly neutralizing antibodies (bnAbs) against HIV-1, and success in preventing SHIV infection following their passive administration, have increased the likelihood that immunotherapeutic strategies can be adopted to prevent and treat HIV-1 infection. However, while broad and potent neutralizing activity is an essential prerequisite, in vivo properties such as good circulatory stability and no-immunogenicity are equally critical for developing a human treatment. In the previous Phase I and Phase II studies, glycoforms of both first generation bnAbs and more recent potent highly mutated bnAbs 10-1074, NIH45-46G54W, 10E8, PGT121, PGT128, PGT145, PGT135, PG9, PG16, VRC01 and b12 have been produced by Agrobacterium-mediated transient transfection of Nicotiana benthamiana and assessed neutralizing activity and following admin- istration in macaques. The results to date indicate that (i) N-glycans within the VL domain impair plasma stability of plant-derived bnAbs and (ii) while PGT121 and b12 exhibit no immunogenicity in macaques after multiple injections, surprisingly VRC01, 10-1074 and NIH45-46G54W elicit high titer anti-idiotypic antibodies following a second injection which specifically bind the administered bnAb or a close family member, and inhibit the bnAb in neutralization assays (iii) both cocktails (VRC01, 10-1074, b12 and 10E8) as well as single PGT121 delivered either intravenously or subcutaneously both pre-and post-challenge administration can protect adult macaques. These results form the basis of the current Phase IIB proposal's dual approach to develop an efficacious bnAb cocktail by (i) performing perinatal protection studies in macaques against SHIV challenge which more closely mimic mother-to-child-transmission (MTCT) (ii) to extend their circulatory retention time and (iii) to identify the T cell epitopes on these highly mutated bnAbs which contribute to their immunogenicity and which could potentially compromising their value for prophylaxis and therapy of HIV-1. In addition, the rapid production of 15 broadly neutralizing plant-derived HIV mAbs in the current study highlights the unique advantages of the transient plant system in terms of speed and versatility, pathogen- free nature and low-tech requirements; particularly in the early developmental stages from cloning to preclinical protection studies.